Production of arylsulfonyl thioureas



United States Patent PRODUCTION OF ARYLSULFONYL THIOUREAS Elmar K.Wilip, Montreal, Quebec, and Avila E. Vendette, Dorion, Quebec, Canada,assignors to Monsanto Chemical Company, St. Louis, Mo., a corporation ofDelaware No Drawing. Application October 6,1952, Serial No. 313,366

Claims priority, application Canada June 17, 1952 8 Claims. (Cl.260397.7)

This invention relates to the production of arylsulfonyl thioureas andmore specifically pertains to a new and improved process for preparingarylsulfonyl thioureas.

Arylsulfonyl thioureas are known compounds. One of the methods by whichthese compoundshave heretofore been made comprises reacting anarylsulfonyl cyanarnide with hydrogen sulfide under pressure.

It has now been discovered thatarylsulfonyl thioureas possessing theformula wherein AR is an aryl radical, can be produced efficiently andeconomically by reacting an arylsulfonyl cyanamide possessing theformula wherein AR is an aryl radical, and M is hydrogen, alkali metalor alkaline earth metal, with a thiolacid in the presence of analiphatic monocarboxylic acid to form a 1-arylsulfonyl-3-acyl thioureaand hydrolyzing this product. Although the reaction can be carried outover a substantial temperature range, for example, from 25 to 100, it ispreferred to carry out the reaction of the thiolacid with thearylsulfonyl cyanamide at 40 to 80 C. It is also preferred to carry outthe hydrolysis step at a temperature of from 60 to 100 C.

The reactions involved in the process of this invention are believed totake place as follows: (A)

, boxylic acid. The excess of the aliphatic monocarboxylic acid can befrom 1-5 moles more than that required for the reaction with thephosphorus pentasulfide. In this, the preferred process, 6-10 moles'ofthe acid will be employed for each mole of phosphorus penta-,

2,738,355 Patented Mar. 13, 1956 sulfide since the reaction ofphosphorus pentasulfide with the acid is as follows:

Ice

amples.

As indicated in the above reaction equations, the thiolacid employed asa reactant need not be a derivative of the lower aliphaticmonocarboxylic acid. In this case, R1 and R may be dilferent alkylradicals and R can contain more than 4 carbon atoms. Furthermore, wherethe thiolacid is not formed in situ any organic thiolacid can beemployed as a reactant. In this case, R can be an aliphatic group suchas the methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl, tridecyl, pentadecyl, heptadecyl, cyclohexyl,cyclopentyl, cycloheptyl groups, as well as such groups containingnon-interfering substituent radicals; or

R can be an aromatic. group such as phenyl, nitrophenyl,

and valeric acids. All these acids possess the formula RiCOOH wherein R1is an alkyl group containing from 1-4 carbon atoms. The thiolacidssuitable for reactants according to the process of this inventionpossess the formula RCOSH wherein R is the residue of an organic acidgroup. As hereinbefore stated R will contain from 1-4 carbon atoms whenthe preferred process is utilized, however any thiolacid can be employedas a reactant where it is not formed in situ. Because they are morereadily available than are the other acids and thiolacids of the groupsabove defined, acetic acid and thiolacetic acid are preferred for theprocess of this invention.

The arylsulfonyl cyanamide compounds useful according to the process ofthis invention as hereinbefore indicated possess the formula wherein Mis hydrogen and alkali metal or alkaline earth metal and AR is an arylradical. The aryl radical can be phenyl, tolyl, xylyl, naphthyl,biphenyl and the like as Well as nuclear substituted aryl radicalswherein the benzene nucleus is substituted with one or more alkyl,aralkyl, aryl, amino, acylamino, nitro, hydroxy, alkoxy, or aryloxygroups. The preferred arylsulfonyl cyanamide'reactants are thosecontaining one of the enumerated groups substituted in the position parato the sulfonyl group.

The hydrolysis of the hypothetical 1-arylsu1fonyl-3- carbonyl thioureaintermediate obtained by the reaction of the thiolacid with thearylsulfonyl cyanamide can be accomplished by any of the well knownmethods. However, the hydrolysis is preferably carried out by addingwater to the reaction mixture and heating the resulting aqueous mixture,preferably to a temperature of from to C. Crude arylsulfonyl thiourea isprecipitated from this aqueous mixture. The resulting crude product canbe readily purified by dissolving it in an aqueous alkaline solution,such as a dilute aqueous solution of sodium carbonate, filtering thissolution, and then acidifying the filtrate to precipitate the purifiedarylsulfonyl thiourea. Dilute aqueous solutions of other alkalinematerials such as sodium bicarbonate, potassium carbonate, potassiumbicarbonate, sodium hydroxide and potassium hydroxide among others canalso be employed.

The process of this invention is particularly applicable to thepreparation of Ni-acylsulfanilyl thioureas, important intermediates inthe preparation of sulfathiazole and other therapeutically usefulsystemic anti-infectives.

The following specific examples are illustrative of the preferred methodof carrying out the reaction, but are not intended to limit the scope ofthe invention.

Example I Into a 2000 ml. flask equipped with a mechanical stirrer,thermometer and air condenser, the following were charged in the ordergiven:

286 g. glacial acetic acid 250 g. calcium acetylsulfanilyl cyanamide 52g. phosphorus pentasulfide The mixture was heated to 60-65 on awater-bath and stirred for four hours. 760 g. of water were then addedto the reaction mixture to hydrolyze the '1-arylsulfonyl-3-methylcarbonyl thiourea intermediates. This aqueous mixture was heatedto 8085 and stirred for two hours. The batch was then cooled to 25 C.and stirring continued for an additional 30 minutes. The crude productwas recovered by filtration and washed with water until the acetic acidcontent of the wash water was below The crude acetylsulfanilyl thioureawas then dissolved in a solution of 20 g. soda ash in 1200 ml. water at40-50", the mixture being stirred for 30 minutes, filtered and theprecipitated impurities washed with 400 ml. water at 5060. Hydrochloricacid was added to the filtrate to a pH of 2.0, and the resultingprecipitate was isolated by filtration and dried at 100. Yield 95 %--M.P. l97199 C.

Example II 50 g. of crude benzenesulfonyl cyanamide was mixed with 100cc. of glacial acetic acid and 20 g. of phosphorus pentasulfide. Anexothermic reaction ensued, the tem perature rising to 50. The mixturewas stirred at 60-65 for one hour, after which 200 ml. of hot water(8090) was added to hydrolyze the intermediate and the whole heated for30 minutes. After cooling, the white precipitate was filtered, washedwith water and dissolved in 400 ml. of 4% sodium carbonate solution.

The resulting solution was treated with l g. of activated carbon,filtered and acidified with hydrochloric acid to a pH of 1.0. Theproduct, benzenesulfonyl thiourea, was filtered and dried to constantweight at 80'-85. The yield was 25 g. (80% of theory) M. P. 1378-1388.Found: N, 12.42%; calc. for C7HsO2N2S2: N, 12.95%.

In a similar manner 4-nitrophenylsulfonyl thiourea can be prepared byreacting 4-nitrobenzenesulfonyl cyanamide with thiolacetic acid in thepresence of glacial acetic acid and hydrolyzing the intermediate withwater at about 80 to 90 C. Any of the other arylsulfonyl cyanamideshereinbefore set forth can be substituted for N l-acetylsulfanilylcyanamide employed in Example I to prepare the corresponding thiourea.

What is claimed is:

1. In the preparation of an arylsulfonyl thiourea the steps compriseheating a reaction mixture containing an aliphatic monocarboxylic acidhaving the formula RiCOOH wherein R1 is an alkyl group containing 1 to 4carbon atoms, an aliphatic thiolacid having the formula RCOSH wherein Ris an alkyl group containing 1 to 4 carbon atoms and an arylsulfonylcyanamide having the formula ArSOzN--CN wherein Ar is an aryl radicaland M is selected from the group consisting of hydrogen, an alkali metaland an alkaline earth metal; thereafter adding water to the resultingreaction mixture and heating this mixture, wherein said process the heatsteps are carried out at a temperature of from40 C. up to but notexceeding about 100 C.

2. A process for preparing an arylsulfonyl thiourea which comprisesheating at a temperature not exceeding about 100 C., the reactantscomprising an arylsulfonyl cyanamide having the formula wherein Ar is anaryl radical and M is a member selected from the group consisting ofhydrogen, an alkali metal and an alkaline earth metal, an anhydrousaliphatic monocarboxylic acid having the formula RiCOOH wherein R1 is analkyl group containing 1 to 4 carbon atoms, and phosphorouspentasulfide; thereafter adding water to the resulting reaction mixture,heating at a temperature of from 40 C. up to but not exceeding 100 C.,cooling the resulting mixture, and recovering the precipitate formed.

3. In the process for preparing an arylsulfonyl thiourea the stepscomprise heating at a temperature not exceeding about 100 C., thereactants comprising an arylsulfonyl cyanamide having the formulaAr-SOrlIT-CN wherein Ar is an aryl radical and M is a member selectedfrom the group consisting of hydrogen, an alkali metal and an alkalineearth metal, an anhydrous aliphatic monocarboxylic acid having theformula RiCOOH wherein R1 is an alkyl group containing 1 to 4 carbonatoms, and phosphorous pentasulfide; thereafter adding water to theresulting reaction mixture and heating at a temperature of from 40 C. upto but not exceeding 100 C., cooling the resulting mixture, andrecovering the precipitate formed.

4. The process of claim 3 wherein the proportions of the reactants are0.2 mole of phosphorous .pentasulfide and 2 to 6 moles of the aliphaticmonocarboxylic acid per equivalent of said cyanamide.

5. In the process for preparing N4-acetylsulfonilyl thiourea, the stepscomprising heating at a temperature not exceeding 100 C., the reactantscomprising calcium acetylsulfonilyl cyanamide, glacial acetic acid, andphosphorous pentasulfide; thereafter adding water to the resultingreaction product and heating this mixture at a temperature of from 40 C.up to but not exceeding 100 C.

6. The process of claim 5 wherein the proportions of the reactants are0.2 mole of phosphorous pentasulfide, 2 to 6 moles of glacial aceticacid for each equivalent of the cyanamide.

7. The process of claim 5 wherein the proportions of the reactants are0.2 mole of phosphorous pentasulfide, 2 to 6 moles of glacial aceticacid for each equivalent of the cyanamide, and the initial heating stepis carried out at a temperature in the range of from about 40 to aboutC. and the second heating step is carried out at a temperature of fromabout 80 to about C.

8. In the process for preparing benzenesulfonyl thiourea the stepscomprising heating at a temperature of from 40 to 80 C., the reactantscomprising benzenesulfonyl cyanamide, glacial acetic acid andphosphorous pentas'ulfide in the proportions of 0.2 mole of said sulfideand '2 to 6 moles of said acetic acid for each equivalent of saidcyanamide; thereafter adding water to the resulting FOREIGN PATENTSreaction products and heating this mixture at a tempera- 55 Denmark 6, gture of from about 80 to about 90 C. 7 901 259 France Oct 30, 1944 5OTHER REFERENCES References C'ted m the file of thls patent I. G. Germanpatent application I 7525 6--Abstracted UNITED STATES PATENTS in AuszugeDeutscher Patent, Anmeldungen," No. 6,

Band I Chernie, page 222 (1947).

2,498,782 Arquet et a1. Feb. 28, 1950 Schiff: Beilstein (Handbuch, 4thed.), vol. 2, p. 230

2,545,764 Charpentier Mar. 20, 1951 (1920).

1. IN THE PREPARATION OF AN ARYLSULFONYL THIOUREA THE STEPS COMPRISEHEATING A REACTION MIXTURE CONTAINING AN ALIPHATIC MONOCARBOXYLIC ACIDHAVING THE FORMULA
 5. IN THE PROCESS FOR PREPARING N4-ACETYLSULFONILYLTHIOUREA, THE STEPS COMPRISING HEATING AT A TEMPERATURE NOT EXCEEDING100* C., THE REACTANTS COMPRISING CALCIUM ACETYLSULFONILYL CYANAMIDE,GLACIAL ACETIC ACID, AND PHOSPHOROUS PENTASULFIDE; THEREAFTER ADDINGWATER TO THE RESULTING REACTION PRODUCT AND HEATING THIS MIXTURE AT ATEMPERATURE OF FROM 40* C. UP TO BUT NOT EXCEEDING 100* C.